Methods for the inhibition of atrophy or for treatment or prevention of atrophy-related symptoms in women

ABSTRACT

This invention relates to a method for inhibition of skin atrophy, or epithelial or mucosal atrophy in women, or to a method for treatment or prevention of symptoms related to said atrophy, said method comprising administering to the woman an effective amount of the compound of formula (I) 
     
       
         
         
             
             
         
       
     
     or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt, an ester thereof or a metabolite thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 10/162,708 filed 6 Jun. 2002, which is a continuation-in-partof International Application No. PCT/FI01/00414 filed 2 May 2001designating the U.S., which was published under PCT Article 21(2) inEnglish as International Publication No. WO 02/07718, and which is acontinuation of U.S. patent application Ser. No. 09/625,199, filed 21Jul. 2000, now U.S. Pat. No. 6,245,819, each application beingincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

This invention relates to a method for the inhibition of skin atrophy,epithelial or mucosal atrophy in women, especially women during or afterthe menopause. The invention also concerns prevention or treatment ofatrophy-related symptoms in women, especially women during or aftermenopause.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference and listed in the Bibliography.

During and after menopause, elderly women commonly develop symptomswhich are due to estrogen deficiency. These symptoms include hotflashes, sweating, insomnia, depression, vaginal dryness, urinaryincontinence, nausea, pain, osteoporosis, coronary heart disease, breasttenderness, oedema, fatigue, decreased sexual activity, as well assubsequent psychosocial problems (Payer, 1990; Rekers, 1990). Inaddition, estrogens are suggested to have neuroprotective effects. Thus,declining estrogen concentrations may negatively affect the mentalactivities of aging women (Schneider & Finch, 1997; Wickelgren, 1997).Estradiol is known to be excellent in the treatment of climactericsymptoms, and its use in the treatment of these symptoms is rapidlyincreasing. However, estrogens cause an increased risk of endometrialand breast cancers. It is possible to decrease the carcinogenicity ofendometrial cancer by sequential progestin administration, but the riskof breast cancer is not diminished by progestins. The carcinogenicityrisk limits the length of estrogen replacement therapy, although itwould be very useful to continue the therapy long term, due to theprotective effects of estrogens in the bone, in the cardiovascularsystem, in the central nervous system, and for urinary symptoms.

“SERM”s (selective estrogen receptor modulators) have both estrogen-likeand antiestrogenic properties (Kauffman & Bryant, 1995). The effects maybe tissue-specific as in the case of tamoxifen and toremifene which haveestrogen-like effects in the bone, partial estrogen-like effect in theuterus and liver, and pure antiestrogenic effect in breast cancer.Raloxifene and droloxifen are similar to tamoxifen and toremifene,except that their antiestrogenic properties dominate. Based on thepublished information, all SERMs are more likely to cause menopausalsymptoms than to prevent them. They have, however, other importantbenefits in elderly women: they decrease total and LDL cholesterol, thusdeminishing the risk of cardiovascular diseases, and they may preventosteoporosis and inhibit breast cancer growth in postmenopausal women.There are also almost pure antiestrogens under development. They aremainly aimed at the treatment of breast cancer (Wakeling & Bowler,1988).

The compound (deaminohydroxy)toremifene, which also is known under thecode FC-1271a or the generic name ospemifene, has relatively weakestrogenic and antiestrogenic effects in the classical hormonal tests(Kangas, 1990). It has antiosteoporosis actions and it decreases totaland LDL cholesterol levels in both experimental models and in humanvolunteers (International patent publications WO 96/07402 and WO97/32574). It also has antitumor activity in an early stage of breastcancer development in an animal breast cancer model. Ospemifene is thefirst SERM which has been shown to have beneficial effects inclimacteric syndromes in healthy women.

The European patent application EP 664124 A1 suggests the use ofraloxifene or related compounds for the inhibition of skin atrophy orvaginal atrophy, especially in postmenopausal women.

SUMMARY OF THE INVENTION

According to one aspect, this invention concerns a method for inhibitionof skin atrophy, or epithelial or mucosal atrophy in women, said methodcomprising administering to the woman an effective amount of thecompound of formula (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptablesalt, an ester thereof or a metabolite thereof.

According to another aspect, this invention concerns a method fortreatment or prevention of symptoms related to skin atrophy, or toepithelial or mucosal atrophy in women, said method comprisingadministering to the woman an effective amount of the compound offormula (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptablesalt, an ester thereof or a metabolite thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1D show changes (from start to 12 weeks' treatment) in thekaryopyknosis index for superficial cells of the vaginal epitelium forthe individuals treated daily with 30 mg ospemifene, i.e. FC-1271a (1A),60 mg FC-1271a (1B), 90 mg FC-1271a (1C), and 60 mg raloxifene (1D).

FIG. 2 shows the effect of 30 mg, 60 mg and 90 mg daily doses ofFC-1271a and raloxifene (daily dose 60 mg) on vaginal dryness, assessedas the individuals' subjective estimates.

DETAILED DESCRIPTION OF THE INVENTION

The methods according to this invention are particularly useful forwomen during or after the menopause. However, the methods according tothis invention is not restricted to women in this age group.

This invention relates particularly to the use of the estrogen receptormodulator ospemifene in women during or after the menopause. Ospemifeneis the Z-isomer of the compound of formula (I) and it is one of the mainmetabolites of toremifene, is known to be an estrogen agonist andantagonist (Kangas, 1990; International patent publications WO 96/07402and WO 97/32574).

The term “metabolite” shall be understood to cover any(deaminohydroxy)toremifene metabolite already discovered or to bediscovered. As examples of such metabolites can be mentioned theoxidation metabolites mentioned in Kangas (1990) on page 9 (TORE VI,TORE VII, TORE XVIII, TORE VIII, TORE XIII), especially TORE VI and TOREXVIII, and other metabolites of the compound.

The use of mixtures of isomers of compound (I) shall also be included inthis invention.

A particular form of atrophy to be inhibited is urogenital atrophy.Symptoms related to urogenital atrophy can be divided in two subgroups:urinary symptoms and vaginal symptoms.

As examples of urinary symptoms can be mentioned micturation disorders,dysuria, hematuria, urinary frequency, sensation of urgency, urinarytract infections, urinary tract inflammation, nocturia, urinaryincontinence, urge incontinence and involuntary urinary leakage.

As examples of vaginal symptoms can be mentioned irritation, itching,burning, maladorous discharge, infection, dyspareunia, leukorrhea,vulvar pruritus, feeling of pressure, postcoital bleeding, vaginaldryness and difficulty in sexual arousal.

The effect of atrophy of the skin is cosmetic, but can also beassociated with pathological conditions such as decreased ability of theskin to undergo wound healing. Atrophy or aging of skin appears aschange of smoothness and texture causing roughness in look and feel onthe outer surface of the skin, change of elasticity of the skineffecting the mechanical properties of the skin, and changes in skinpigmentation. Skin aging in postmenopausal women can also be measured asdecrease in the mitotic rate of keratinocytes, changes in dermalthickness and decrease in glucosaminoglucans and soluble collagen whichare linked to the moisture content of the skin.

The new and surprising effect of ospemifene was found in a clinicalstudy. In this study, raloxifene (60 mg/day) or ospemifene at differentdoses were given to elderly female volunteers for a period of 3 months.At the dose levels of 30, 60 and 90 mg of ospemifene daily, asignificant decrease in vaginal atrophy was observed. An improved sexualactivity was also reported. These properties are new and unique amongthe known selective estrogen receptor modulators (SERMs) and indicatethat ospemifene at the doses from 25 mg to slightly lower than 100 mgdaily, particularly 30 to 90 mg daily, can be successfully used toalleviate symptoms derived from atrophy, especially urogenital atrophyin women during or after the menopause. Furthermore, ospemifene has asuperior profile of estrogenic and antiestrogenic effects when comparedto any known antiestrogen or SERM compound.

Ospemifene has been found to alleviate many symptoms related tourogenital atrophy, both urinary symptoms and vaginal symptoms.Ospemifene has also been found to alleviate sexual dysfunction and toincrease the sexual activity. Types and causes of female sexualdysfunction are particularly desire disorders, arousal disorders,orgasmic disorders and painful intercourse (dyspareunia). Most of theseare due to hormonal reasons, especially to reduced estrogen andtestosterone concentrations. Vaginal atrophy is one of the main causesof female sexual dysfunction and will typically develop after themenopause when the estrogen concentrations decrease. Typically thisleads to painful intercourse, which indirectly may influence on any typeof sexual dysfunction, including psychological causes. In elderly womenvaginal atrophy is often the main reason for decreased sexual activity.(Spector and Carey, 1990).

Estrogens and testosterone are useful pharmaceutical treatments ofvaginal dryness and it is not surprising that pure antiestrogens likeraloxifene cause vaginal dryness. Subsequently, the patients are notsatisfied with the treatment which causes painful intercourse and willstop the therapy.

The compound (I) can according to this invention be administered byvarious routes such as oral, topical, transdermal, intravaginal orsubcutaneous routes, of which oral or transdermal administration routesare the most preferable.

Suitable preparation forms include for example tablets, capsules,granules, powders, suspensions, syrups and transdermal formulations,ointments, creams, or gels. Also subcutaneous implants may be useful forprolonged use. For vaginal local delivery vaginal creams, gels,vagitories, vaginal tablets, pessaries or vaginal rings are preferred.

EXPERIMENTS

A clinical phase I-II study was carried out to study the effects ofospemifene on endometrial thickness, endometrial pathology, (biopsytaken by curettage as described by Vuopala et al, 1982) and cervicalsmear in healthy postmenopausal female volunteers in the age range 55 to69 years. Tolerability and pharmacokinetics were also assessed.Raloxifene (60 mg daily) was used as reference. Ospemifene was givenperorally at the doses of 30, 60 and 90 mg daily. There were 29volunteers at each dose level, as well as in the raloxifene group.Ospemifene was administered in gelatine capsules containing either 30,60 or 90 mg of ospemifene. The thickness of the endometrium wasevaluated by ultrasonography using a Hitachi EUB-405 instrument. Thevaginal epithelium was assessed by karyopyknosis index which is a wellknown assessment method among the skilled persons. In this method, thevaginal fraction of the cervical smears is estimated as the percentageof the number of cells from different layers: the parabasal cell layer;the intermediate cell layer; and the superficial cell layer.Estrogenicity is seen by a shift towards superficial cell fraction. Inpostmenopausal women this fraction usually is close to zero andestradiol treatment increases the fraction close to 100. Samples weretaken before and after the treatment (at 3 months).

The vaginal dryness symptoms were also assessed by using a visualanalogue scale where the volunteers themselves recorded their subjectiveestimates. The scale is based on a 100-mm line on paper. The left endrepresents no symptom and the right end the worst possible symptom. Thechange from pre-treatment to 3 months estimates was assessed andconsidered to be indicative of the treatment efficacy.

There were no differences in the demographic data between the treatmentgroups in any of the pre-treatment measurements.

Assessment of the Vaginal Estrogenic Effect of Ospemifene

Table 1 below shows the change in maturity index for parabasal cells(MI 1) and maturity index for superficial cells (MI 3), after 3 months'administration of varying doses of ospemifene or raloxifene.

TABLE 1 Change in maturity index for parabasal cells and maturity indexfor superficial cells MI 1 MI 1 MI 3 MI 3 Compound and dose mean Sd meansd Ospemifene, 30 mg, −40 42 +12.4 13.6 (n = 21) Ospemifene, 60 mg, −2639 +5.5 13.4 (n = 20) Ospemifene, 90 mg, −48 44 +12.5 14.0 (n = 22)Raloxifene, 60 mg, −2 34 −0.3 4.1 (n = 19) parabasal cells (MI 1): index100 no estrogenicity; index 0 full estrogen superficial cells (MI 3):index 100 full estrogen; index 0 no estrogenicity

In FIGS. 1A to 1D there are shown changes (from start to 12 weeks'treatment) in the karyopyknosis index for superficial cells of thevaginal epithelium for the individuals treated daily with 30 mgospemifene (1A), 60 mg ospemifene (1B), 90 mg ospemifene (1C), and 60 mgraloxifene (1D). In the Figures, the code FC-1271a is used instead ofthe generic name ospemifene.

Cervical smear assessments indicate that no one in the raloxifene group(FIG. 1D) had a significant change from baseline to post-treatment inthe karyopyknosis index for superficial cells. Most of the individualsin the ospemifene groups had slight increases in the index, but in restof the subjects the estrogenic effect was very weak, if measurable atall. In all cases the increase was small (<40 except for one case whichwas 45 in the 90 mg group) when compared to estradiol which is known toincrease the index virtually by 100. A weak but statisticallysignificant estrogenic effect in the cervical smear was thereforedocumented. No pathological changes were seen in any sample.

FIG. 2 shows that raloxifene caused only a minor decrease on vaginaldryness, assessed by the individuals' subjective estimate, while all theospemifene dosage levels indicated a clear decreasing effect. The doselevel 60 mg ospemifene daily gave the best result.

Assessment of the Endometrial Estrogenic Effect of Ospemifene

Ospemifene had a weak estrogenic effect on endometrial histology. Thiseffect is clearly weaker than that seen with estrogen replacementtherapy. There were no malignant findings in the endometrium. Thethickness of the endometrium as assessed by ultrasonography showed onlya minor, statistically not significant, increase in the thickness(average 0.2 mm, 0.5 mm and 0.5 mm) at the dose levels of 30, 60 and 90mg, respectively. The measured values were always smaller than 8 mm,which is considered to be a thickness which is indicative for aphysiologically significant estrogenicity of SERMs like tamoxifen (Hannet al, 1997; Lahti et al, 1993).

Effect on Urogenital Atrophy and Symptoms Related Thereto

In the clinical phase I and II studies, 241 posmenopausal women havebeen treated with ospemifene. 77 were treated with 25-30 mg, 78 with50-60 mg, 78 with 90-100 mg and 8 with 200 mg daily dose of ospemifene.In the control groups, 47 were treated with placebo and 29 withraloxifene. Some of the subjects reported spontaneously alleviation ofthe symptoms associated with urogenital atrophy. The symptoms includeboth vaginal and urinary symptoms such as vaginal discomfort withirritation, itching, burning, smarting, dyspareunia, postcoitalbleeding, vulvar itching and/or malodorous discharge and leukorrhea. Theurinary symptoms alleviated in individual cases include urinaryincontinence, recurrent urinary tract infections, micturition disorders,urinary frequency, nocturia, sensation of urgency, urge incontinence andinvoluntary urinary leakage. Also, the clinicians reported cases wheresigns of urogenital atrophy, such as vaginal pallor, petechiae,friability, vaginal dryness, vaginal mucosa atrophy and ulceration werealleviated by ospemifene.

Effect on Sexual Activity

In the clinical study, where the effects of ospemifene on quality oflife and cardiovascular parameters were studied, the patients were askedfor sexual activity. The questionnaire included “worsening” or “noeffect” on sexual activity. Improvement on sexual activity was notasked. When 70 patients had been followed up for 6 weeks, 27 of them hadspontaneously reported to the investigators increased sexual activity.Similar reports were independently obtained from different centers ofthe study. This strongly suggests that ospemifene has a positive effecton the sexual activity and quality of life.

The results indicate that ospemifene has a unique pharmacologicalprofile with regard to estrogen-like effects on vaginal atrophy andinsignificant endometrial effects. In these tissues the estrogenicity ismarkedly lower than that of the known SERMs tamoxifen and toremifene,but higher than that of raloxifene. In contrast to other SERMs, it doesnot cause menopausal symptoms. Actually ospemifene at the doses of 25 mgor more, and especially 30-90 mg daily, alleviated such symptoms.Ospemifene has an especially beneficial effect in that it decreasesvaginal dryness and sexual dysfunction. Based on the present data, theoptimal clinical dose is expected to be higher than 25 mg daily andlower than 100 mg daily. A particularly preferable daily dose is foundin the range 30 to 90 mg. At the higher doses (100 and 200 mg daily),ospemifene shows properties more similar to those of tamoxifen andtoremifene. Ospemifene is an especially valuable drug because it has anexcellent tolerability. In addition, ospemifene decreases total and LDLcholesterol, increases HDL cholesterol, and prevents osteoporosis andearly stage breast cancer. The present invention suggests thatospemifene and other compounds of formula (I) can be also used duringmenopause as hormone replacement therapy instead of estrogens, which areknown to increase the risk of breast and endometrium cancers.

It will be appreciated that the methods of the present invention can beincorporated in the form of a variety of embodiments, only a few ofwhich are disclosed herein. It will be apparent for the expert skilledin the field that other embodiments exist and do not depart from thespirit of the invention. Thus, the described embodiments areillustrative and should not be construed as restrictive.

BIBLIOGRAPHY

Delmas P D, Bjarnason N H, Mitlak B H, Ravoux A C, Shah A S, Huster W J,Draper M, Christiansen C: Effects of raloxifene on bone mineral density,serum cholesterol concentrations, and uterine endometrium inpostmenopausal women. N Engl J Med 337: 1641-1647, 1997

Ettinger B, Genant H K, Cann C E: Long-term estrogen replacement therapyprevents bone loss and fractures. Ann Intern Med 102: 319-324, 1985

Hann L E, Giess C S, Bach A M, Tao Y, Baum H J, Barakat R R: Endometrialthickness in tamoxifen-treated patients: correlation with clinical andpathologic findings. Am J Roentgenol 168: 657-661, 1997

Gustafsson J-Å: Estrogen receptor β—getting in on the action? NatureMedicine 3: 493-494, 1997

Kangas L: Biochemical and pharmacological effects of toremifenemetabolites. Cancer Chemother Pharmacol 27: 8-12, 1990

Kauffman R F, Bryant H U: Selective estrogen receptor modulators. DrugNews Perspect 8: 531-539, 1995

Lahti E, Blanco G, Kauppila A, Apaja-Sarkkinen M, Taskinen PJ,Laatikainen T: Endometrial changes in postmenopausal breast cancerpatients receiving tamoxifen. Obstet Gynecol 81: 660-664, 1993

Palkowitz A D, Glasebrook A L, Thraser K J, Hauser K L, Short L L,Phillips D L, Muchi B S, Sato M, Shetler P K, Cullinan G J, Pell T R,Bryant H U: Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene: a novel, highly potent, selectiveestrogen receptor modulator. Med Chem 40: 1407-1416, 1997

Payer L: The menopause in various cultures. In: A portrait of themenopause. Expert reports on medical and therapeutic strategies for the1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, N.J.,USA, 1991. pp 3-22

Rekers H: Matering the menopause. In: A portrait of the menopause.Expert reports on medical and therapeutic strategies for the 1990s. Ed.Burger H & Boulet M, Parthenon Publishing, Park Ridge, N.J., USA, 1991.pp 23-43

Schneider L S, Finch C E: Can estrogens prevent neurodegeneration. Drugs& Aging 11: 87-95, 1997

Spector I P, Carey M P: Incidence and prevalence of sexual dysfunctions:a critical review of the empirical literature. Archives of SexualBehaviour 19: 389-408, 1990.

Vuopala S, Kauppila A, Mikkonen M, Stenbäck F: Screening of asymptomaticpostmenopausal women for gynecological malignancies, with specialreference to endometrial sampling methods. Arch Gyncol 231: 119-127,1982

Wakeling A E, Bowler J: Biology and mode of action of pureantiestrogens. J Steroid Biochem 30: 1-6, 1988

Wickelgren I: Estrogen stakes claim to cognition. Science 276: 675-678,1997

1. A method for the treatment of urinary symptoms related tourogenital_(—) atrophy in women, said method comprising administering toa woman in need therof an effective amount of ospemifene or apharmaceutically acceptable salt thereof wherein the urinary symptomsare micturition disorders, dysuria, hematuria, urinary frequency,sensation of urgency, urinary tract infections, urinary tractinflammation, nocturia or involuntary urinary leakage.
 2. The methodaccording to claim 1 wherein the compound is ospemifene.
 3. The methodaccording to claim 1 wherein the ospemifene is administered orally,topically, transdermally, intravaginally or subcutaneously.
 4. Themethod according to claim 2 wherein the ospemifene is administered in adaily dose varying in the range of 25 to 100 mg.
 5. The method accordingto claim 2 wherein the ospemifene is administered in a daily dosevarying in the range of 30 to 90 mg.
 6. The method according to claim 2wherein the ospemifene is administered in a daily dose of 60 mg.
 7. Themethod according to claim 5 wherein the ospemifene is administeredorally.
 8. The method according to claim 6 wherein the ospemifene isadministered orally.
 9. The method according to claim 1 wherein thewoman is a postmenopausal woman.
 10. The method according to claim 2wherein the woman is a postmenopausal woman.
 11. The method according toclaim 8 wherein the woman is a postmenopausal woman.
 12. The methodaccording to claim 1 wherein the urinary symptom is dysuria.
 13. Themethod according to claim 2 wherein the urinary symptom is dysuria. 14.The method according to claim 5 wherein the urinary symptom is dysuria.15. The method according to claim 11 wherein the urinary symptom isdysuria.